Osteoporosis is a disease that results in the weakening of bone and an increase in the risk of fracture. It has been reported that American females over the age of 50 have about a 50% chance of breaking a bone during their lifetime, and a 40% chance of breaking either a hip, vertebra or wrist. Post-menopausal women lose about 1-3% of their bone mass for each of the first 5-7 years after menopause. Osteoporosis is believed to contribute to about 1.5 million fractures a year in the United States, including about 700,000 spinal fractures and about 300,000 hip fractures. According to the Mayo Clinic, about 25% of the people over 50 who fracture a hip die within a year of the incident. The risk of breaking a bone for an osteoporotic individual doubles after the first fracture. The risk of breaking a second vertebra for an osteoporotic individual increases about four-fold after the first spinal fracture.
Human bone comprises hard mineralized tissue and softer collagenous tissue. The combination of these tissues provides bone with both a structural, weight-bearing capability and a shock-absorption capability. As the bone ages, however, the collagenous portion of the bone is slowly mineralized, thereby making the entire bone more brittle. To compensate for this, bone constantly undergoes a process called “remodeling” in which older, more mineralized bone is replaced by new, more collagenous bone.
Bone remodeling is undertaken by two competing processes: bone formation and bone resorption. Bone formation is largely achieved by bone-forming cells called osteoblasts, while bone resorption is largely achieved by bone-eating (bone-resorbing) cells called osteoclasts. In the normal desired situation, the rate of bone formation is essentially equal to the rate of bone resorption, so that bone mass in the body is maintained.
Osteoporosis occurs when the rate of bone resorption exceeds the rate of bone formation. The rate of bone resorption is largely dependent upon the local production of osteoclasts.
Current treatments for osteoporosis have focused upon arresting the activity of the osteoclast cells. In particular, osteoporosis therapy has focused upon administering drugs called “anti-resorptive agents” or ARA's. The most common classes of anti-resorptive drugs include estrogen, selective estrogen receptor modulators (SERMs), biphosphonates, calcitonin, osteoprotegrin (OPG), cathespin K and statins. Current products include FOSAMAX® (alendronate) in the U.S., Biphosphonate DIDRONEL® (etidronate), and ACTONEL® (risedronate).
Despite the promise provided by these anti-resorptives, there still remain serious issues. First, many anti-resorptives act in a manner that wholly eliminates osteoclast activity. Thus, the delicate balance between bone formation and bone-resorption is again upset, and older, highly mineralized tissue remains within the bone. Although this has the effect of increasing bone mineral density (BMD), the bone that remains is fragile and prone to microdamage.
Second, many of the anti-resorptives are administered systemically, through either oral or intravenous means. Accordingly, side effects associated with systemic administration are often seen. For example, the systemic administration of hormone replacement therapy (“HRT”) has been associated with an elevated cancer risk. In response to this concern, some anti-resorptive drugs, such as biphosphonates, have been engineered to be selective for bone tissue. However, in many cases, the amount of such tissue selective drug that actually reaches bone is often less than 100%.
In recent years, the roles of estrogen and pro-inflammatory cytokines in osteoporosis have become much more clear. For example, in post-menopausual women, it is believed that osteoporosis occurs due to a decrease in estrogen. Because estrogen is believed to block the production of pro-inflammatory cytokines, a depleted level of estrogen is believed to lead to an increase in pro-inflammatory cytokines, and consequently to increased osteoclast production and increased bone resorption.
Pacifici, R., “Cytokines, estrogen, and postmenopausal osteoporosis—the second decade,” Endocrinology, 139(6): 2659-2661 (1998), teaches that estrogen prevents bone loss by blocking the production of proinflammatory cytokines by bone marrow and bone cells. Pacifici further discloses that IL-1 and TNF-α are the most powerfully locally produced stimulators of bone resorption and are well recognized inhibitors of bone formation. Pacifici concludes that there is now substantial evidence supporting the hypothesis that a network of estrogen-regulated cytokines is responsible for the changes in bone turnover and the loss of bone induced by estrogen deficiency, and that it is likely that during the current decade the development of orally active, tissue selective cytokine inhibitors will lead to new strategies for the prevention and treatment of postmenopausal osteoporosis. As Pacifici discloses only oral administration, Pacifici does not disclose the local administration of selective cytokine inhibitors.
Allali, F., et al., “Increase in bone mineral density of patients with spondyloarthropathy treated with anti-tumour necrosis factor alpha,” Ann. Rheum. Dis., 62: 347-349 (2003) reports of an increase in the bone mineral density (BMD) of patients with spondyloarthropathy (SpA) treated with anti-tumor necrosis factor α (TNF-α). Patients in the Allali study received infliximab by infusion. Allali suggests that a benefit of the anti-TNF-α therapy on BMD in patients with SpA may be through an uncoupling effect on bone cells. Allali does not disclose the local administration of selective cytokine inhibitors.
Published U.S. Patent Application No. U.S. 2003/0007972 (“Tobinick I”) discloses methods for treating bone metastases in humans by locally administering a therapeutically effective dose of specific cytokine inhibitors. Tobinick discloses local administration routes designed for perilesional or intralesional use in proximity to the site of tumor metastases to bone, including subcutaneous, intramuscular, interspinous, epidural, peridural, parenteral or perispinal administration.
Tobinick, E. L., “Targeted etanercept for treatment-refractory pain due to bone metastasis: two case reports,” Clin. Ther., 25(8): 2279-88 (2003) (“Tobinick II”) discloses that etanercept delivered by targeted SC injection may be of clinical benefit in selected patients with treatment-refractory pain caused by bone metastases.
Tobinick does not disclose the intraosseous administration of selective cytokine inhibitors, nor does Tobinick disclose treating osteoporotic bone.
In sum, no prior art reference discloses an intraosseous injection of a highly specific cytokine antagonist (i.e., inhibitor) inhibitor to increase i.e., the BMD of an uncoupled resorbing bone.
Because of the limitations of anti-resorptives, some investigators have focused on increasing bone-formation activity as a means of treating osteoporosis. For example, teriparatide (hPTH 1-34), a fragment of parathyroid hormone, has been found to increase the rate of bone formation and has been approved for treating osteoporosis. However, it must be taken as a daily intravenous injection. In addition, according to Biskobing, D. M., “Novel therapies for osteoporosis,” Expert Opinion Invest. Drugs, 12(4): 611-621 (2003), the FDA has recommended a maximum of 2 years of treatment due to concern over long-term safety in light of the development of osteosarcoma in rats treated with high-dose teriparatide. See also Vahle, J. L., et al., “Skeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid hormone (1-34) for 2 years and relevance to human safety,” Toxicol Pathol., 30(3): 312-21 (2002).
Other investigators have proposed administering selected growth factors as a means of increasing the rate of bone formation. For example, Rodan, G. A. and Martin, T. J., “Therapeutic approaches to bone diseases,” Science, 289: 1508-1514 (2000) (“Rodan”) proposes that growth factors such as insulin-like growth factor (IGF), transforming growth factor-β (TGF-β) fibroblast growth factor (FGF), and bone morphogenic proteins (BMPs) have come under consideration as potential treatments for bone diseases, especially severe osteoporosis. Rodan further noted that future developments might yield ways to overcome conventional difficulties by confining these growth factors to bone sites through osteoblast-targeted regulation of their production, or, perhaps, by gene therapy. However, some of these growth factors may also have an effect of upregulating osteoclast activity as well.
Because of its potential as a bone growth agent, a number of investigators have investigated the use of fibroblast growth factor (FGF) as a bone forming agent.
Nakamura, K., et al., “Local application of basic fibroblast growth factor into the bone increases bone mass at the applied site in rabbits,” Arch. Orthop. Trauma Surg., 115(6): 344-346 (1996), (“Nakamura”) discloses that a single local injection of basic fibroblast growth factor (bFGF) into a rabbit ilium causes local bone growth.
Lane, N. E., et al., “Basic fibroblast growth factor forms new trabeculae that physically connect with pre-existing trabeculae, and this new bone is maintained with an anti-resorptive agent and enhanced with an anabolic agent in an osteopenic rat model,” Osteoporosis Int'l., 14: 376-82 (2003) (“Lane”) discloses that a systemic administration of bFGF induces bone growth in the proximal tibia of ovarectomized (“OVX”) rats. Lane further reports that the bone growth caused by the bFGF appears to resorb in these OVX rats after the administration period. Lastly, Lane reports that a post-FGF systemic administration of hPTH (1-34) was effective in maintaining the bone growth attributable to the FGF administration.
Goodman, S. et al., “Effects of local infusion of TGFbeta on bone ingrowth in rabbit chambers,” J. Biomed. Mat. Res. (Appl Biomater), 53: 475-479 (2000) teaches the local delivery of TGF-B in rabbit chambers.
Some investigators have advocated a combination therapy including a bone-forming agent and an anti-resorptive. For example, Biskobing further noted that others have recommended using teriparatide concomitantly with an anti-resorptive. Rodan, “Therapeutic approaches to bone diseases,” Science, 289: 1508-1514 (2000) concluded that far less attention has been paid to promoting bone formation with, for example, growth factors or hormones, an approach that would be a valuable adjunct therapy to patients receiving inhibitors of bone resorption.
U.S. Pat. No. 6,554,830 (“Chappius”) discloses a surgical anchor for anchoring within a vertebral body, having a plurality of passages for the delivery of bone cement therethrough. Specified bone bonding cements appear to include polymethylmethacrylate and cranial plast.
U.S. Published Patent application No. U.S. 2002/0010471 (“Wironen”) discloses methods of injecting materials into osteoporotic bones. In particular, Wironen is directed to a device for injecting materials into bone comprising a threaded catheter and an internal removable trocar. The subject device may also have disposed on one end an attachment means, e.g., Luer-lock fitting, for attaching a syringe, whereby a syringe of any filler can then be attached to the luer-lock fitting and the filler material can then be squirted through the catheter and into the marrow cavity. One filler that may be used is a composition comprising mineralized particles (e.g., corticocancellous chips or “CCC” of a size from about 100 to 1000 microns, e.g., 500 to 850 microns), ground bone powder (for example, from about of 100 to 1000 microns, e.g., 500 to 850 microns), a biactive ceramic such as a non-degradable or degradable hydroxyapatite, bioactive glass, and the like, osteogenic paste, chondrogenic paste, carrier associated Growth Factors, carrier associated mineralized particles, morsellized skin or other tissue, Fibrin powder, Fibrin/plasminogen glue, Demineralized Bone Matrix (DBM)/glycerol, DBM/pleuronic F127, DBM/CCC/F127, polyesters, polyhydroxy, compounds, polyvinyl compounds, polyamino compounds, polycarbonate compounds, and mixtures of one or more of these compositions. Wironen further teaches that the resulting repair using this bone paste composition leads to a mass of mineralized tissue that is vascularized. When non-degradable hydroxapatite is used, the mass is stable and not as subject to degradation by the osteoporotic patient. Wironen does not disclose anti-resorptive materials.
Accordingly there is a need to provide improved methods of treatment of osteoporosis and related diseases.